The long-term objective of this work is to eliminate brucellosis as a biothreat. Brucella infection may occur through water, food sources and through exposure to infected animals. Brucella species induce abortions in domestic animals and severe, incapacitating illness in humans, with symptoms of undulating fever, night sweats, fatigue, anorexia, weight loss and arthritis. While human brucellosis can be treated through antibiotic regimens, symptoms of Brucellosis are flu-like and could lead to delayed diagnosis. Brucella remains a major source of human disease worldwide. It is estimated that as few as 10 bacteria can induce human infection via the respiratory tract. Natural or engineered genetic alteration of Brucella species could lead to higher fatality rates which, coupled with the extremely high infectivity of Brucella spores, could result in the development of more deadly bioweapons. To date, no vaccines have been approved for use in humans. Vaccination of domestic cattle with B. abortus strain RB51 has effectively eradicated the disease from domestic herds but is abortogenic to cows and has been implicated in human infection of livestock handlers. The prevalence of Brucella abortus infection among elk and bison populations of Yellowstone National Park has raised concerns about reintroduction of B. abortus into domestic cattle. Brucella abortus has recently been found in populations of feral pigs in South Carolina. To both eradicate the incidence of natural Brucella infection and eliminate the threat of Brucella as a bioweapon, we propose to 1) optimize the immunogenicity of several genetic vaccine candidates, isolated from a random genetic expression library, in a murine model and 2) test the ability of these candidates to protect mice from an aerosol model of Brucella infection.